Preventing influenza infection with aminobicyclo(3.2.2)nonanes

ABSTRACT

1,104,058. Antiviral compositions. SMITH KLINE &amp; FRENCH LABORATORIES. 2 Nov., 1966 [9 Nov., 1965; 20 Dec., 1965; 12 May, 1965; 10 Aug., 1366], No. 49224/66. Heading ASB. [Also in Division C2] Antiviral compositions comprise novel bicycloamines of the formulµ (where n is zero or 1; one A is NH 2 , CH 2 NH 2 , CH(CH 3 )NH 2  or NHCH 3  and the others are H; one B is NH 2 , CH(CH 3 )NH 2  or NHCH 3  and the others are H; and one C is CH 2 NH 2  and the others are H) or the known 6-aminomethylbicyclo [3.2.2] nonane, or acid-addition salts thereof and carriers. They are administered orally or intranasally. A specified ingredient is 3-aminobicyclo [3.3.1] nonane hydrochloride.

United States Patent 3,439,102 PREVENTING INFLUENZA INFECTION WITH AMINOBICYCLO{3.2.21NONANES Alfred W. Chow, Radnor, Pa., assignor to Smith Kline 8: French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Continuation-impart of application Ser. No. 507,057, Nov. 9, 1965. This application Aug. 10, 1966, Ser. No. 571,430

Int. Cl. A61]; 27/00; C07c 87/40 US. Cl. 424325 7 Claims ABSTRACT OF THE DISCLOSURE Amino, aminomethyl, and a-aminoethylbicyclo[3.2.2] nonanes and their salts are prepared, formulated, and administered to animals to combat influenza infections.

This application is a continuation-in-part of copending application Ser. No. 507,057, filed Nov. 9, 1965, now abandoned.

This invention relates to aminobicyclo[3.2.2]nonanes having antiviral activity. In particular, the invention relates to bicyclo[3.2.2]nonanes substituted at the 1,2,3, or fi-position with an amino or substituted amino group.

The chemical compounds of the invention are represented by the following structural formula:

methyl, ethyl, propyl, hexyl, acetyl, isobutyryl, and benzoyl.

The invention also includes a method of ameliorating the effects of and a method of preventing viral infections by means of a compound of Formula I. In addition, the invention includes a method of ameliorating the effects of and a method of preventing viral infections with a compound of Formula III, or a pharmaceutically acceptable acid addition salt thereof.

where one B group is CHNH2 7 0 and the other B groups are hydrogen, and R is hydrogen or methyl.

Hce

The compounds of Formula I are prepared in the following manner:

1-aminobicyclo[3.2.2]nonane is prepared by treating 1- chlorobicyclo[3.2.2]nonane [Helv. Chim. Acta, 41, 1191 (1958)] with lithium and the resulting compound carbonated with carbon dioxide to give the l-carboxylic acid. The acid is then converted to the l-amino compound by conventional methods including the Schmidt Reaction (sodium azide and sulfuric acid) and the Curtius Reaction (formation of the azide, transformation to the isocyanate, and hydrolysis to the amine).

The 2-amino compound is prepared by the Ritter Re action, i.e. treatment of 2hydroxymethylbicyclo[2.2.2] octane [Chem. Ber. 88, 144 (1955 with acetonitrile and sulfuric acid. The resulting 2-acetamidobicyclo[3.2.2] nonane is then hydrolyzed with acid to give the 2-amino compound.

The 3-amino compound is prepared by condensing cyclohepta-3,5-dienone [1. Org. Chem. 30, 2109 (1965)] with ethylene in a bomb to form the Diels-Alder product 111.

0 III The double bond is reduced by catalytic hydrogenation, the ketone is converted to the oxime, and the oxime reduced to the 3-amine by catalytic hydrogenation or with lithium aluminum hydride.

The 6-amino compound is prepared by condensing cyclohepta-1,3-diene [Chem. Ber. 95, 2567 (1962)] with ethyl acrylate in a bomb to give theDiels-Alder product IV. The double bond is reduced by catalytic hydrogenation, the ester C H OOC saponified with base, and the acid converted to the amine by means of the Schmidt or Curtius Reactions.

The compound of Formula II where the B group at the 6position is CH NH and the other B groups are hydrogen is described in Chem. Ber. 89, 1972 (1956). The other compounds Within the scope of formula II are prepared by conventional methods. The compound where the B group at the 1-position is CH NH is prepared from the carboxylic acid by conversion to the acid chloride, then to the amide, and finally by conventional reduction. The compound with the B group at the 2-position is CH NH is prepared by oxidizing the Z-hydroxy compound to a 2-ketone, and running the Wittig reaction with methoxymethylene triphenylphosphorane to give ultimately the 2- carboxaldehyde. Reaction with hydroxylamine and reduction of the oxime gives the product. The 3CH NH compound is also prepared by this series of steps, starting with the 3-ket0ne.

The compounds Where B is on; (IJHNH2 are prepared as follows: The compound where the CH3 (IJHNH2 group is at the l-position are prepared by treating the carboxylic acid with methyl lithium, converting the resulting methyl ketone to the oxime with hydroxylamine,

the acid to the product as described above using the methyl lithium procedure. The

(3H3 3-CHNH2 compound is prepared by converting the 3-ketone to the carboxylic acid by means of the Wittig procedure and silver nitrate oxidation, and then converting the acid to the product by the above-described procedure. The

compound is prepared from the carboxylic acid in the same manner.

The compounds where the HNH2 group is at the 1, 2, or 3 positions are considered part of the present invention.

The various primary amino compounds, prepared as described above, are readily converted into alkyl, dialkyl, or acyl derivatives by well-known procedures. A lower alkylamine is prepared by treatment of the amine with a lower alkyl halide or sulfate. An acylarnine is prepared by treatment with an acyl halide or anhydride. An acylarnine is also reduced to an alkylamine with lithium aluminum hydride. Dilower alkylamines are prepared by acylating an alkylamine, and then reducing the acylalkylamine with a reagent such as lithium aluminum hydride. A methylamino compound is prepared by reaction of methanol with a bicyclic isocyanate, followed by reduction of the resulting carbamate with lithium aluminum hydride.

The basic amine compounds of the invention may be converted to any of a variety of pharmaceutically acceptable acid addition salts by adding an acid, either as such or in the form of an alcoholic, ethereal, or acetone solution, to a solution of the basic compound. Among the pharmaceutically acceptable acids which may be used to form the salts are hydrochloric, which is preferred, sulfuric, hydrobromic, citric, pamoic, maleic, cyclohexylsulfamic, nitric, acetic, tartaric, and succinic.

Since certain of the carbon atoms in the claimed bicyclo [3.2.2]nonanes possess assymetric carbon atoms, it will be apparent that these compounds exist in the form of racemic mixtures. Inasmuch as separation of racemic mixtures by various methods is known to the art of organic chemistry, the present invention is intended to embrace the racemic mixtures as well as the separated optically active forms.

The antiviral compounds of the invention are particularly active against influenza viruses. The compounds of the invention are used and the methods of the invention are practiced by administering to a warm-blooded mammal, either before or immediately after infection has occurred, an effective amount of an antiviral compound. The compounds are active at a dose level of 1-100 mg./ kg. of subject mammal per day. The compounds are best administered either orally in the form of tablets or capsules, or intranasally in the form of a nasal spray or nose drops. The free base or a pharmaceutically acceptable acid addition salt may be used. The compositions are formulated in a manner well-known to pharmaceutical chemists, utilizing standard pharmaceutical excipients such as lactose, starch, terra alba, magnesium stearate, calcium sulfate, glyceryl mono or distearate, gelatin, or wax. The oral compositions may contain 50-500 mg. of active compound.

The nasal spray or nose drops can be a 2-10% preparation. The 2-amino and 6-amino compounds have been found to cause a 55-90% increase in the survival of mice infected with influenza A Ann Arbor strain at subcutaneous dosages of 25-100 mg./ kg. of test animal. The 6-aminomethyl compound has been found to cause a 45- increase in the survival in mice infected with influenza A at oral and subcutaneous dosages of 156-25 mg./kg. and 42-75% in mice infected with influenza A swine strain at oral and subcutaneous dosages of 625-25 mg./ kg.

A tablet may have the following composition:

Z-aminobicyclo[3.2.2]nonane hydrochloride Magnesium stearate 2.5

Starch 15 Terra alba Granulate with syrup or 5% gelatin solution terra alba, q.s. ad 300 A nasal solution may have the following composition:

6-aminomethylbicyclo [3 .2.2] nonane hydrochloride percent w./v 7.45 1 Eucalyptol, N.F. percent v./v 0.020 Saccharin sodium percent w./v 0.050 Thimerosal, N.F. do 0.001 Potassium biphthalate do 0.130 Sodium citrate do 0.200 Purified water, q.s. ad do 100.000

Equivalent to 5% base A capsule may have the following composition:

Mg. 2-aminobicyclo[3.2.2]nonane hydrochloride 200 Lactose, starch, or terra alba 200 The following examples are intended to illustrate the preparation of the compounds of the invention. Various minor modifications in the compounds and in the processes for preparing them which occur to one skilled in the art of synthetic organic chemistry are intended to be part of the present invention.

EXAMPLE 1 l-aminobicyclo[3.2.2]nonane Lithium wire (4.8 g., 0.7 mole) is placed under 50 ml. of mineral oil, the system is purged with dry nitrogen, and powdered under anhydrous conditions. The mineral oil is removed under nitrogen and the lithium sand is washed and then replaced with 50 ml. of dry cyclohexane. Onehalf of a solution of 15.8 g. (0.1 mole) of l-chlorobicyclo[3.2.2]nonane in 50 ml. dry cyclohexane is added and the mixture, while being stirred, is heated to 90. An exothermic reaction starts and this is maintained by the addition of the other half of the solution of the halide. The suspension is heated for 1 hour at reflux under a positrve nitrogen pressure, then cooled, and 100 ml. of dry pentane added. Carbon dioxide (dried) is passed into the stirred suspension for two hours. The excess lithium is destroyed by addition of alcohol and then water. Following the addition of 150 ml. of ether, the aqueous phase is acidified with hydrochloric acid and the solid which precipitates is extracted with ether. The ethereal extract is evaporated to give the crude l-carboxylic acid. Sublimation 111 vacuo gives the purified acid.

To a solution of 7.2 g. (0.043 mole) of the acid in 100 ml. of chloroform is added 60 ml. of concentrated sulfuric acid, followed by 12 g. (0.060 mole) of sodium azide in small portions. The reaction mixture is heated at 55 for 6 hours and poured onto ice. After removal of chloroform in vacuo, the residual liquid is made basic with 10% sodium hydroxide and extracted with ether. The ethereal extract is dried and evaporated to give the title amine. An ethereal solution of the amine is treated with ethereal hydrogen chloride to give the amine hydrochloride.

EXAMPLE 2 Z-aminobicyclo [3 .2.2]nonane Acetonitrile (0.97 g., 0.0235 mole) is charged into the reaction flask and cooled to C. Conc. sulfuric acid (6.3 g., 0.0642 mole) is added dropwise with stirring at the same temperature. To the resulting clear, cooled solution is added dropwise 3.0 g. (0.0214 mole) of Z-hydroxymethylbicyclo[2.2.2]octane. The reaction mixture is allowed to reach room temperature and is stirred for 3 hours. The reaction mixture is poured over 43.6 ml. of 10% sodium hydroxide containing ice. The white, oily solid which forms is extracted with benzene and ether. The extracts are dried, the solvent stripped under vacuum to give a light yellow oil, and the oil is distilled at 135/ 0.75 mm. to give 2-acetamidobicyclo[3.2.2]nonane.

The amide (2.3 g., 0.0127 mole) is refluxed overnight in 23.0 ml. of cone. hydrochloric acid With stirring under nitrogen. Upon cooling, a white solid comes out of solution, M.P. 255 dec. Recrystallization from acetonitrile gives the hydrochloride salt of the title amine, M.P. 303 dec. The free base is obtained by dissolving the salt in water, making the solution basic, extracting with ether, and drying and evaporating the solvent.

EXAMPLE 3 3-aminobicyclo [3 .2.2] nonane Cyclohepta-3,5-dienone (8.0 g., 0.074 mole) is reacted with ethylene in a bomb at 170 for 24 hours. The reaction mixture is evaporated to give crude bicyclo[3.2.2] non-6-en-3-one.

The crude olefin (5.9 g., 0.044 mole) is hydrogenated over 0.5 g. of platinum oxide in hexane on a Parr shaker for one hour. Filtration and concentration of the filtrate gives the crude bicyclo[3.2.2]nonan-3-one [1. Am. Chem. Soc. 87, 2183 (1965); Chem. Ber. 91, 1525 (1958)].

A solution of 7.5 g. of hydroxylamine hydrochloride, 30 ml. of water, and 30 ml. of 10% sodium hydroxide is adjusted to pH 6.5-7.0. To this solution is added a solution of the above ketone (3.0 g., 0.022 mole) dissolved in 10 ml. of 95% alcohol. The mixture is heated to 70 and kept at this temperature for 0.5 hour. The reaction mixture is cooled and extracted with several portions of ether. The ethereal extract is dried and evaporated in vacuo to give the oxime as an oil.

The oxime (1.53 g., 0.01 mole) is taken up in 150 ml.

of methanol to which a small amount of ethereal hydrogen chloride has been added. This solution is by drogenated over 0.5 g. of platinum oxide at 60 and 60 psi for 16 hours.

The reaction mixture is filtered and the filtrate concentrated to give the title amine hydrochloride. The free base is obtained in conventional manner as described above.

EXAMPLE 4 6-aminobicyclo [3.2.2] nonane A mixture of 7.0 g. (0.075 mole) of cyclohepta-1,3- diene and 9.4 g. (0.094 mole) of ethyl acrylate are reacted in a bomb at 170 for 45 hours. The product is distilled at 144-145/27-28 mm. to give ethyl bicyclo[3.2.2]non- 8-ene-6-carboxylate.

3.0 grams (0.0154 mole) of ethyl bicyclo[3.2.2]non- 8-ene-6-carboxylate is hydrogenated on a Parr shaker over 0.3 g. of platinum oxide in hexane for 3 hours. The saturated nonane product is distilled at l27144/29 mm.

Ethyl bicyclo[3.2.2]nonane-6-carboxylate (2.0 g., 0.01 mole) is hydrolyzed with 4.0 g. of potassium hydroxide in methanol under reflux for 3 /2 hours. The acid is purified by reprecipitation, MP. 117 dec.

A mixture of 1.1 g. (0.0063 mole) of bicyclo[3.2.2] nonane-6-carboxylic acid, 15 ml. of reagent chloroform, and 6.4 ml. of cone. sulfuric acid are stirred for a short period. 4.65 grams (0.0071 mole) of sodium azide is added over a 25 minute period. The reaction mixture is stirred at 56-58 for 5 /2 hours. Ice is added and the chloroform is stripped under vacuum. The aqueous phase is made alkaline and extracted with ether. After being dried, the ether solution of the title amine is acidified with ethereal hydrogen chloride. White solid is formed. The hydrochloride salt is recrystallized from methanolether, M.P. 280 dec.

EXAMPLE 5 Z-dimethylaminobicyclo [3 .2.2] nonane 2-aminobicyclo[3.2.2]nonane (1.5 g.) is mixed with 0.5 mole of formic acid and 0.22 mole of 35% formaldehyde solution. The mixture is heated for 12 hours on the steam bath, 50 ml. of cone. hydrochloric acid is then added, and the mixture evaporated to dryness in vacuo. To the residue is added 200 ml. of 1 N sodium hydroxide. The product is obtained by extraction with ether and drying and evaporating the ether. The pure product is obtained by distillation or by conversion from a previously purified hydrochloride salt.

EXAMPLE 6 6-methylaminobicyclo [3.2.2] nonane Bicyclo[3.2.2]nonane-6-carboxylic acid (Example 4, 6.47 g., .0385 mole) is stirred with 90 ml. of thionyl chloride at room temperature under a calcium chloride tube for 16 hours. The thionyl chloride is stripped 00? in vacuo, azeotroping the last traces with benzene. The acid chloride is dissolved in 300 ml. of acetone and chilled in an icesalt bath to 05. A solution of 2.9 g. (.044 mole) of sodium azide in 29 ml. of water is added slowly to the stirred solution of acid chloride. The cloudy orange mixture is stirred at 5 for 15 minutes and then poured into 400 ml. of ice water. The mixture is extracted with a total of 500 ml. of toluene, washed several times with a total of 400 ml. of water, dried over magnesium sulfate, and filtered. The clear yellow solution of the acid azide is heated on a steam bath for an hour and then refluxed for 1 hour. The toluene is evaporated to give the 6- isocyanate.

The isocyanate (3.23 g.) is dissolved in 60 ml. of methanol and the solution is then refluxed for 2 hours. The solvent is evaporated in vacuo, 50 ml. of dry tetrahydrofuran is added to the resulting carbamate, and the mixture is refluxed with 0.76 g. of lithium aluminum hydride for four hours. The reaction mixture is decomposed with water and filtered, and the filtrate evaporated to give the title methylamino product. The pure product is obtained either by distillation or by conversion from a previously recrystallized hydrochloride salt.

EXAMPLE 7 3-acetamidobicyclo 3 .2.2] nonane 3-aminobicyclo[3.2.2]nonane (2.73 g.) is allowed to stand overnight with 5 g. of acetate anhydride in ml. of pyridine. The reaction mixture is then diluted with ice water and the amide product removed by filtration or extracted with a solvent such as ether or chloroform. Recrystallization yields the pure product.

EXAMPLE 8 3-(N-ethylacetamido)bicyclo[3.2.2]nonane A solution of 1.81 g. of the amide of Example 7 in 50 ml. of dry tetrahydrofuran is refluxed for 2 hours with 0.45 g. of 53.5% sodium hydride. A solution of 1.56 g. of ethyl iodide in 25 ml. of dry tetrahydrofuran is added to the cooled reaction mixture which is then refluxed for twelve hours. A small amount of water is cautiously added with cooling, the solution is filtered, and more of the tetrahydrofuran evaporated in vacuo. A further quantity of water is added, the alkaline solution is extracted with ether, and the extracts dried and evaporated to give the title product.

7 EXAMPLE 9 3-diethylaminobicycle [3.2.2] nonane A solution of 2.09 g. of the N-ethylacetamide compound of Example 8 in 100 ml. of dry tetrahydrofuran is refluxed with 0.5 g. of lithium aluminum hydride for 12 hours. The excess hydride is decomposed by the cautious addition of water, with cooling. The solution is filtered, the filtrate extracted with ether, and the ether extracts evaporated to give the diethylamino product. Reduction of the 3-acetamido product of Example 7 in the same manner gives the 3-ethylamino compound.

EXAMPLE l-propylaminobicyclo [3 .2.2] nonane To a stirred solution of 250 ml. of absolute alcohol, 25 g. of sodium bicarbonate, and 17.6 g. of l-aminobicyclo[3.2.2]nonane hydrochloride is added 17.0 g. of propyl iodide. The mixture is warmed and maintained at a temperature sufficient to cause the evolution of carbon dioxide until the gas evolution ceases. The mixture is cooled and filtered, and the solvent evaporated. Sodium hydroxide (10%) is added to the residue, and the basic mixture extracted with ether. The ether extracts are dried and evaporated to give an oil which is distilled to give the title product.

EXAMPLE 1 1 l-aminomethylbicyclo [3 2.2] nonane A solution of 5.04 g. (.03 mole) of bicyclo[3.2.2]nonane-l-carboxylic acid in 25 ml. of thionyl chloride is re fluxed for 2 hours and then allowed to stand overnight at room temperature. The excess thionyl chloride is evaporated in vacuo, the residual oil is taken up in benzene, and the solution further evaporated to give the acid chloride.

This acid chloride is dissolved in ml. of dry tetrahydrofuran and the solution added dropwise to an ice-cold solution of cone. aqueous ammonia (ca. 75 ml.). After stirring for 1 hour, water is added, and the amide either removed by filtration or extracted with an organic solvent.

To a slurry of 3.04 g. of lithium aluminum hydride in 400 ml. of refluxing tetrahydrofuran is added in portions, over 1 hour, 3.34 g. of this amide, all under nitrogen. The mixture is heated at reflux for 24-48 hours, cooled, and the excess hydride decomposed by the cautious addition of water. The resulting white slurry is filtered, the filter cake washed with ether, and the filtrates combined and evaporated in vacuo to give the title aminomethyl product.

EXAMPLE 12 2-aminomethylbicyclo [3 .2.2]nonane To a solution of 4.06 g. (0.029 mole) of 2-hydroxybicyclo[3.2.2]nonane in 50 ml. of acetic acid is added dropwise over a period of time 3.2 g. (0.032 mole) of chromic anhydride in 2.5 ml. of water and 50 ml. of acetic anhydride, with cooling. The mixture is stirred 4 hours at room temperature, poured into water, and extracted with pentane. The pentane extracts are washed, dried, and evaporated to give bicyclo[3.2.2]nonan-Z-one.

A stirred suspension of g. (0.0584 mole) of methoxymethyl triphenylphosphonium chloride in 100 ml. of tetrahydrofuran and 100 ml. of diglyme is treated dropwise with 52.5 ml. (.05 mole) of ethereal n-butyl lithium in a nitrogen atmosphere, and the mixture allowed to stir for 3 hours at To the resulting deep red solution is added dropwise a solution of 3.45 g. (0.025 mole) bicyclo[3.2.2]nonan-2-one in 20' ml. each of tetrahydrofuran and diglyme. After stirring for 4 hours at 25, the tetrahydrofuran is removed by heating on the steam bath, 100 ml. of diglyme is added, and the mixture is refluxed for 7 hours. The mixture is cooled, concentrated to onehalf volume in vacuo, and treated with methyl bromoacetate to remove any triphenylphosphine. After stand- 8 ing 12 hours, the solid is filtered off, the filtrate washed with water, and the dried organic layer evaporated to give an oil. Column chromatography over alumina gives the 2-methoxymethylene compound.

This vinyl ether is allowed to stand for 15 minutes at room temperature in a saturated solution of ether in perchloric acid, poured into aqueous sodium bicarbonate and extracted with ether. Evaporation of the dried ether extracts gives the 2-carboxaldehyde.

To a solution of 9.38 g. of hydroxylamine hydrochloride in 40 ml. of water and 40 ml. of 10% aqueous sodium hydroxide is added a solution of 4.15 g. of the Z-aldehyde in 50 ml. of alcohol. The mixture is heated at 70- 80 for 15 minutes, filtered hot, and then diluted with 175 ml. of cold Water. The precipitate is collected and dried to give the 2- aldehyde oxime.

To a slurry of 1.75 g. of lithium aluminum hydride in 150 ml. of refluxing tetrahydrofuran is added over 20 minutes a solution of 3.55 g. of the oxime in 75 ml. of tetrahydrofuran. The mixture is heated at reflux for 3 hours, cooled, and the excess hydride decomposed by cautious addition of water. The resulting white slurry is filtered, the filter cake washed with ether, and the combined filtrates dried and evaporated to give the title 2- aminomethylbicyclo[3.2.2]n0nane. The 3-aminomethy1 compound is prepared in the same manner from the 3- ketone.

EXAMPLE 13 l-(u-aminoethynbicyclo [3.2.2] nonane Bicyclo[3.2.2]nonane-l-carboxylic acid (4.95 g., 0.0295 mole) is dissolved in m1. of dry tetrahydrofuran and, with stirring under nitrogen, 31 ml. (0.062 mole) of 2 N methyl lithium in ether is added over 3 to 4 minutes. The mixture is refluxed overnight and cooled to room temperature. Water (25 ml.) is added, and the product extracted with ether. After drying over magnesium sulfate, the ether is removed to yield bicyclo[3.2.2]non-1-yl methyl ketone.

To a mixture of 5.8 g. of this ketone, 3.22 g. (0.0463 mole) of hydroxylamine hydrochloride, and 15 ml. of ethanol are added, portionwise with stirring, 3 ml. of water and 5.9 g. (0.147 mole) of powdered sodium hydroxide. The reaction mixture is stirred and refluxed for 15 minutes and then poured into an ice cold solution of 20 ml. (0.240 mole) of concentrated hydrochloric acid in ml. of Water. The colorless solid is filtered and washed with water. After drying over phosphorus pentoxide, the oxime of the ketone is obtained.

A solution of 3.85 g. of the oxime in 50 ml. of tetrahydrofuran is added to a stirred suspension of 2.93 g. (0.077 mole) of lithium aluminum hydride in 75 m1. of ether. The mixture is stirred and refluxed overnight. After cooling to room temperature, 7 ml. (7.0 g., 0.389 mole) of water is added dropwise, and the mixture is stirred 1 hour at room temperature. The solid is filtered and washed well with ether. The ether is dried with solid potassium hydroxide and then with magnesium sulfate, and the product ot-aminoethyl compound obtained by removal of the ether. The hydrochloride salt is obtained by bubbling dry hydrogen chloride into an ether solution of the product amine until precipitation is complete, and then purifying by recrystallization.

EXAMPLE 14 2- (oz-aminoethyDbicyclo[3.2.2]nonane To a solution of 2.74 g. of bicyclo[3.2.2]nonane-2-carboxaldehyde and 11.32 g. of silver nitrate in a mixture of 45 ml. of water and 35 ml. of absolute ethanol is added, dropwise with stirring over a 2 hour period, a solution of 4.2 g. of sodium hydroxide in 75 ml. of water. The resulting mixture is stirred overnight, filtered, extracted with ether, acidified, and again extracted with ether. Drying and evaporation of the ether gives the 2-carboxylic acid.

where one A group is NRR and the other A groups are hydrogen; R is hydrogen, lower alkyl, acetyl, isobutyryl or benzoyl; and R is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt thereof.

2. A method of preventing influenza infections comprising administering to a warm-blooded mammal an efiective, but nontoxic, amount of a compound according to claim 1, in which the A group at the 2-position is Nit-I and the other A groups are hydrogen.

3. A method of preventing influenza infections comprising administering to a warm-blooded mammal an eflective, but nontoxic, amount of a compound of the formula where one B group is CHNHZ and the other B groups are hydrogen, and R is hydrogen or methyl; or a pharmaceutically acceptable acid addition salt thereof.

4. A method of preventing influenza infections as claimed in claim 3, where the B group at the 6-position is CH NH and the other B groups are hydrogen.

5. An oral dosage unit in the form of a tablet or capsule for the prevention of influenza infections in warm-blooded mammals comprising -500 mg. of a compound according to claim 1, in which R is hydrogen or methyl and R is hydrogen, and a pharmaceutical carrier.

6. An oral dosage unit in the form, of a tablet or capsule for the prevention of influenza infections in Warmblooded mammals comprising 50500 mg. of a compound as defined in claim 3 and a pharmaceutical carrier.

7. An oral dosage unit in the form of a tablet or capsule for the prevention of influenza infections in warmblooded mammals comprising 50500 mg. of a compound as defined in claim 4 and a pharmaceutical carrier.

References Cited UNITED STATES PATENTS 3,355,355 11/1967 Stedman 167--65.2

ALBERT T. MEYERS, Primary Examiner.

J. GOLDBERG, Assistant Examiner.

US. Cl. X.R. 

